p53 protein expression in transitional mucosa and adenocarcinomas of the colorectum.

Transitional mucosa, the nonneoplastic mucosa adjacent to colorectal adenocarcinomas, exhibits some morphologic and histochemical abnormalities. It is unclear, however, whether transitional mucosa is a preneoplastic or reactive phenomenon. Though normal p53 functions as a tumor suppressor, p53 gene alterations have been proposed as a step in malignant transformation, and aberrant p53 protein expression has been described in a high percentage of colonic adenocarcinomas. Since p53 protein normally has a short half-life, immunohistochemical detection of the protein is considered to be evidence of abnormal p53 expression. We analyzed p53 protein expression immunohistochemically on frozen tissue samples of transitional mucosa, normal mucosa, and tumor from 20 cases. In all 20 cases the transitional mucosa and normal mucosa failed to express p53, while 13 of 20 adenocarcinomas showed positive immunoreactivity characterized by intense nuclear staining. There was no correlation between tumor stage and p53 expression. The absence of staining for p53 protein in TM does not support the theory that transitional mucosa is a preneoplastic phenomenon.

P-glycoprotein expression in gastroesophageal adenocarcinomas, their metastases, and surrounding mucosa: a mapping study.

Previously, we identified P-glycoprotein in primary gastroesophageal adenocarcinomas and in adjacent mucosa. This study is a further investigation of P-glycoprotein expression in adenocarcinomas and benign mucosa. Sixteen resection specimens were studied (seven for gastric adenocarcinoma, seven for esophageal adenocarcinoma, one for adenocarcinoma at the gastroesophageal junction, and one for severe dysplasia in Barrett's esophagus). Multiple samples of tumor and mucosa were submitted according to a specimen diagram. Lymph node and distant metastases were studied when available. P-glycoprotein expression was identified in paraffin-embedded tissues by immunohistochemistry using monoclonal antibody C219 and was scored as the percentage of cells stained. P-glycoprotein was identified in six of 16 resection specimens. Intratumoral variability of C219 score was noted in three resections. No increase in expression was identified in lymph node or distant metastases as compared with primary tumors or in the invasive margin of the tumor as compared to the center. For every case in which tumors expressed P-glycoprotein, it was also diffusely present in all types of benign gastric and Barrett's mucosa, both adjacent to and distant from (up to 8 cm) the tumor. We also studied biopsies from 10 patients with Barrett's esophagus who did not have carcinoma. P-glycoprotein was only focally present in one of the 10 biopsies. Mucosa expressing P-glycoproteins may be the substrate from which a P-glycoprotein positive tumor arises.

Mucinous carcinomas of the colon and rectum. An analysis of 62 stage B and C lesions.

The significance of a large extracellular mucinous component in colorectal adenocarcinomas continues to be controversial. We studied 62 stage B and C mucinous carcinomas defined by 60% or greater mucinous component. Sixty of these patients had matched nonmucinous adenocarcinoma controls. Patients with mucinous carcinomas with a residual adenoma had a significantly greater survival than those who did not. Overall, no difference was noted in 5-year survival between patients with mucinous carcinoma and nonmucinous adenocarcinoma (64% each). However, when the stages were considered separately, patients with stage B mucinous carcinoma fared significantly worse and had more local sites of treatment failure. We speculate that patients with stage B mucinous carcinoma may have a worse prognosis owing to the extra-cellular mucin, which may make a complete surgical extirpation more difficult.

Histologic observations and P-glycoprotein expression in gastric and esophageal adenocarcinomas treated with preoperative chemotherapy.

To describe histologic changes associated with chemotherapy response, we reviewed biopsy and resection specimens from 52 patients with locally advanced esophageal or gastric adenocarcinoma who were treated with preoperative chemotherapy, followed by resection. P-Glycoprotein expression in the adenocarcinomas was also determined with the use of antibody C219. Significant changes in morphologic appearance of the tumor between prechemotherapy and postchemotherapy samples was noted in 17 tumors (32.7%). The most frequent changes observed in these 17 tumors were a decrease in tumor cellularity and an increase in dense fibrosis in comparison with the prechemotherapy specimen. In signet-ring cell carcinomas, the intracytoplasmic mucin vacuoles were often smaller after chemotherapy, making tumor cells more difficult to identify. Another finding observed in tumors that showed histologic alteration after chemotherapy was the formation of large mucin pools that contained lymphocytes and macrophages. The remaining 35 tumors showed similar histologic features in prechemotherapy and postchemotherapy specimens. P-Glycoprotein was identified in 15 (29.4%) of 51 specimens after chemotherapy. P-Glycoprotein content of the residual tumors did not correlate with stage, degree of differentiation, or clinically determined chemotherapy response. We concluded that chemotherapy-induced changes in morphology were frequent in patients with upper gastrointestinal tract adenocarcinomas treated with preoperative chemotherapy. These changes should be recognized as they may cause difficulties in both gross and histologic evaluation of the extent of tumor in postchemotherapy resection specimens. The response of adenocarcinomas to this chemotherapy protocol does not appear to be linked to P-glycoprotein expression.

Prognostic factors in esophageal squamous carcinoma. A study of histologic features, blood group expression, and DNA ploidy.

The authors studied 69 squamous carcinomas of the middle or lower esophagus to evaluate prognostic factors. Clinical and histologic parameters that were evaluated included weight loss, esophageal obstruction at presentation, site, gross configuration, degree of tumor differentiation, vascular invasion, the status of resection margins, and stage. Blood group antigen (BGA) expression in the tumors was determined immunohistochemically and compared with blood type and antigen reactivity in adjacent normal mucosa. A loss of BGA expression was seen in 27 tumors. This finding was correlated with high stage but was not significantly linked to survival. DNA ploidy was determined by flow cytometry of paraffin-embedded tissues. Forty-one of 52 tumors were aneuploid, and 14 had two or more separate aneuploid populations. However, survival was not correlated with ploidy status. The degree of differentiation and stage of the tumors were the only two independently significant prognostic indicators in this study.

Exophytic signet-ring cell carcinoma of the colorectum.

Previous studies have assessed colorectal signet-ring cell carcinomas of the linitis plastica variant but not of the exophytic subtype. We retrospectively reviewed 20 cases of colorectal signet-ring cell carcinoma of the exophytic subtype (greater than 50% signet-ring cells). The patients ranged in age from 14 to 79 years (mean, 51.8 years); 10 were male; 17 were white; and three were black. Ten tumors were colonic (eight, right sided; two, left sided) and 10 were rectal; seven were stage B and 12 were stage C. One patient presented with distant metastases. Eleven of 16 tumors assessed by flow cytometry were diploid. Parenchymal hepatic metastases developed in only two patients. The overall 5-year survival rate was 36%, and matched cases did not vary significantly in survival from typical nonmucinous adenocarcinomas. There was a trend toward poorer survival for patients with advanced-stage tumor. Survival was not affected by primary site, ploidy, presence of vascular/lymphatic invasion or residual adenoma, or percentage of extracellular mucin or signet-ring cells. Our cases were somewhat lower stage than literature cases of signet-ring cell carcinoma of the lintis plastica variant.

The gastric juice urea and ammonia levels in patients with Campylobacter pylori.

The authors studied gastric juice ammonia and urea nitrogen levels to determine how they are altered by gastric Campylobacter pylori (CP) infection. Patients with chronic gastritis (20), peptic ulcer (24), hepatic cirrhosis (10), chronic renal failure (13), or gastric remnant (20) were included. Endoscopic biopsy specimens stained with the Warthin-Starry stain were evaluated for the presence of CP. Blood and gastric juice analysis was performed for 11 of the patients with chronic renal failure and 37 patients from the remaining groups. CP was identified in gastric biopsies from 50 of 87 (57.5%) patients, including 87.5% with peptic ulcer and 40-50% of those with chronic gastritis, cirrhosis, chronic renal failure, or gastric remnant. CP infection had no effect on blood urea nitrogen or blood ammonia levels in any group of patients. The urea nitrogen level of gastric juice was higher in patients with chronic renal failure than in other groups but was not related to CP infection. CP infection was associated with a significant increase in gastric juice ammonia levels, both in patients with chronic renal failure (23.3 mmol/L vs. 2.90 mmol/L; [P less than 0.05]) and in other groups (5.48 mmol/L vs. 1.26 mmol/L [P less than 0.0001]). The authors conclude that elevation of gastric juice ammonia level is an indicator of gastric CP infection.

Histologic parameters and DNA ploidy as predictors of survival in stage B adenocarcinoma of colon and rectum.

Stage B adenocarcinomas of colon (61 carcinomas) and rectum (44 carcinomas) were retrospectively reviewed in order to define prognostic indicators and to determine if they are different for tumors arising at the two sites. Parameters evaluated included the substage of the tumor, histologic grade, presence of vascular/lymphatic invasion, residual adenoma or extracellular mucin, and tumor cell DNA content as determined by flow cytometry of paraffin-embedded tissues. Five-year survival was 81.0% for patients with colonic and 87.5% for those with rectal tumors. DNA ploidy was a significant predictor of overall and disease-free survival in patients with rectal adenocarcinomas (improved survival for those with diploid tumors) but not in those with colonic tumors and not in the two groups combined. The degree of differentiation of the tumor was prognostically significant in the colonic group and for the groups combined but not in the rectal group. There was a trend toward better survival in substage B1 tumors, as compared with substages B2 and B3, particularly in rectal neoplasms. Other histologic parameters did not predict survival. We conclude that the prognostic indicators in colonic adenocarcinoma seem to differ from those of adenocarcinoma arising in the rectum and that DNA ploidy has a significant impact upon outcome in stage B rectal adenocarcinomas.

Monoclonal antibody C219 detection of the multidrug-resistant protein P-glycoprotein in routinely processed tissues: a study of 36 cases of ovarian carcinoma.

P-glycoprotein is a membrane protein found in high levels in multidrug-resistant (MDR) tumor cells and is associated with in vitro and clinical resistance of neoplasms to a wide variety of structurally unrelated oncolytic agents. We retrospectively investigated the presence of P-glycoprotein in 36 patients with treated, high grade ovarian carcinomas by using a murine monoclonal antibody (C219). The patients were selected on the basis of their complete response (11 patients) or nonresponse (25 patients) to chemotherapy. Routinely processed tissue sections from pre- and postchemotherapy surgical tissue samples were processed by a standard immunohistochemical method. Sections of tumor from both pre- and postchemotherapy specimens from the responder group were all negative, as were the prechemotherapy specimens from the nonresponder group. Four of the 25 (15%) nonresponders' postchemotherapy tissues were positive, predominantly in areas of histologically undifferentiated tumor. The cellular localization of P-glycoprotein in normal, untreated tissues was also investigated using C219, and its presence in various luminal epithelia of the gastrointestinal tract, kidney, and liver are consistent with its proposed normal function as a toxin/drug-export protein. Our overall results indicate that P-glycoprotein can be detected in routinely processed tissues by standard methods. The presence of P-glycoprotein in some patients with treated ovarian carcinomas is associated with nonresponse to standard chemotherapy treatment.

Sarcomatoid carcinoma of the stomach. A report of three cases with immunohistochemical and ultrastructural observations.

The authors report three cases of sarcomatoid carcinoma arising in the stomach. This uncommon tumor is characterized by a mixture of malignant epithelial and spindle cell elements. All three tumors were large (average diameter, 5 cm) and infiltrated deep into the stomach wall. Two of the tumors had a polypoid configuration; the third was ulcerated and endophytic. Intestinal metaplasia was present adjacent to the tumor in all cases, with dysplasia in two. Immunohistochemical studies showed positivity for cytokeratin, carcinoembryonic antigen, and epithelial membrane antigen in the epithelial component of all tumors, and Leu-M1 was positive in the epithelial component of one. The spindle cell components contained vimentin, and in tumor 2, the spindle cell component was also positive for desmin. Two tumors showed focal positivity for cytokeratin in the spindle cells immediately adjacent to the epithelial component. Ultrastructurally, the spindle cell component of two tumors was composed of undifferentiated cells without specific epithelial or mesenchymal features. The third tumor contained occasional cells with features of myofibroblasts.

Ovarian carcinomas with transitional cell carcinoma pattern.

The authors report 88 cases of ovarian carcinoma containing areas of transitional cell carcinoma (TCC). The tumors were found in women 28-76 years old (mean, 51 years). Fifteen patients presented with stage II, 59 with stage III, and 14 with stage IV disease. Ten neoplasms were composed of only TCC, 48 were predominantly TCC, and 30 had foci of TCC but the predominant component was serous, endometrioid, undifferentiated, or unclassified adenocarcinoma. After the primary resection of the neoplasm, 76 patients received chemotherapy, 4 received chemotherapy and radiotherapy, and 5 received radiotherapy only; 2 refused further treatment and 1 patient died immediately after the first operation. Estimated five-year survival rates were 37% for the entire group and 41% for those who received chemotherapy. Favorable prognostic indicators, statistically significant, were low clinical stage, predominant TCC in the primary tumor, and a negative second-look operation. Other prognostic indicators were the amount of residual tumor after the first operation and tumor differentiation. When the primary neoplasm was predominantly TCC, another prognostic indicator was the type of carcinoma present in the metastases. Five-year follow-up shows that 56% of the patients whose metastases were predominantly TCC have no evidence of disease, whereas only 7% of the patients whose metastases are predominantly non-TCC are disease-free. The authors' study indicates that ovarian carcinomas containing predominant TCC pattern have an excellent response to different chemotherapy regimens. Tumor recurrences and lack of response to chemotherapy are often associated with a change in the histologic appearance of the metastatic lesion.

Transitional mucosa of colon. A morphological, histochemical, and immunohistochemical study.

We studied alterations in the transitional mucosa of the colon in 18 cases of primary colonic adenocarcinoma (4 from the cecum; 4, the ascending colon; 5, the descending colon; 2, the sigmoid colon; and 3, the rectum). One patient had 2 separate primary tumors. Formalin-fixed, paraffin-embedded sections were studied in all cases, and tissues fixed in methacarn fixative were available in 9. Sections of tumor and transitional mucosa were compared with those of normal mucosa distant from the tumor. Sections were stained with hematoxylin-eosin, Masson's trichrome, and alcian blue at a pH of 0.9 (sulfomucin) and at a pH of 2.5 (sialomucin and sulfomucin). Immunoperoxidase stains for collagen type IV (basal lamina) were also performed. Transitional mucosa showed morphological alterations, including increase in mucosal thickness and crypt distortion. An increase in lamina propria fibrosis was noted in transitional mucosa in 3 cases. Abnormal mucin content, consisting of a predominance of sialomucin, was noted in transitional mucosa in 12 cases. In one of these, sialomucin was predominant in both transitional and normal mucosa. No alterations in the thickness of the subepithelial collagen table were noted. Collagen type IV staining was effective in demonstrating an increase in lamina propria vascularity in transitional mucosa in 11 specimens.

Expression of a multidrug resistance gene in esophageal adenocarcinoma. Correlation with response to chemotherapy and comparison with gastric adenocarcinoma.

The resistance of malignant tumors to chemotherapy is often associated with overexpression of the multidrug resistance gene MDR. Its gene product, P-glycoprotein, acts as a drug efflux pump for chemotherapeutic agents. The authors studied MDR expression in 28 adenocarcinomas arising in Barrett's esophagus (EAs) using a monoclonal antibody directed against this gene product. The results were compared with MDR expression in 27 gastric adenocarcinomas (GAs). P-glycoprotein was detected in both tumor and normal mucosa in 7 of 27 GAs and in 6 of 10 EAs that were resected without prior chemotherapy. Chemotherapy was given before surgical resection in 18 of the EAs studied. Five patients had a partial response to chemotherapy, and one had a complete eradication of his carcinoma; all of these tumors were negative for P-glycoprotein. Of 12 patients without chemotherapy response, 6 had tumors that expressed P-glycoprotein. The authors conclude that P-glycoprotein is present in EAs and GAs before exposure to chemotherapy. The presence of P-glycoprotein in tumors usually correlates with its presence in the adjacent mucosa. Its presence in tumor cells may be an indicator of lack of sensitivity to chemotherapy.

The prevalence of Campylobacter pylori in gastric biopsies from cancer patients.

The prevalence of Campylobacter pylori (CP) in gastric biopsies from cancer patients has not been previously studied. We reviewed 112 gastric biopsies from 78 adult patients at a cancer hospital. The patients had a previous history or current diagnosis of gastric or esophageal carcinoma (26 patients), gastric lymphoma (15 patients), gastric stromal tumor (three patients), carcinoid tumor (two patients), nongastroesophageal malignancy (29 patients), or atrophic gastritis with nonhealing ulcer (three patients). The biopsies were stained with hematoxylin-eosin (H&E), Warthin-Starry, Giemsa, and Brown-Hopps. CP was identified in 30 biopsies from 26 patients. Eighteen of the biopsies showed active gastritis, nine showed chronic inflammation/intestinal metaplasia, and one contained an ulcer. CP was also identified in two stomachs bearing tumors (one adenocarcinoma, one carcinoid tumor). Active gastritis was present without CP in nine biopsies, including three from patients on chemotherapy and one from a patient with bile reflux. The organism was detected by the Warthin-Starry stain in 30 biopsies. The Giemsa stain was positive in 27, Brown-Hopps in 27, and H&E in 24. Non-CP bacteria were identified in the Brown-Hopps in seven cases and were mistaken for CP in H&E stains in two. We conclude that CP is frequently found in the cancer patient with active gastritis and is an occasional finding in tumor-bearing stomachs. Special stains are useful in identifying CP, and the Brown-Hopps is helpful in distinguishing CP from other bacteria.

Gastric parietal cell carcinoma with an unusual, lymphoma-like histologic appearance: report of a case.

We report a case of gastric carcinoma with an unusual histologic appearance and type of cellular differentiation. The tumor was resected from an 85-yr-old man who presented with epigastric pain and monoclonal gammopathy. The tumor was antral in location and transmurally infiltrated the stomach wall. Histologically, the tumor closely resembled a lymphoma with diffuse poorly cohesive sheets of tumor cells interspersed with histiocytes. Immunohistochemical study, however, clearly demonstrated the epithelial nature of this tumor. Electron microscopy also revealed evidence of epithelial differentiation and features of parietal cell differentiation. In this report, we describe the light and electron microscopic findings, immunohistochemical staining properties, and DNA flow cytometric findings of this tumor and briefly review the literature on parietal cell carcinomas.

Anaplastic and sarcomatoid carcinoma of the small intestine: a clinicopathologic study.

Carcinomas involving the jejunum and ileum are rare tumors. During a review of small intestinal neoplasms, six primary carcinomas of jejunum or ileum with an anaplastic and sarcomatoid histology were identified. At presentation, three of the patients had symptoms related to metastatic disease and three had symptoms referable to the local tumor. The tumors were large (greater than 4.5 cm in diameter), usually endophytic masses composed of large cells with eosinophilic cytoplasm, anaplastic nuclei, and prominent nucleoli. In many areas, the cells had a spindled configuration. Mucin positivity was identified in all six cases. Electron microscopic findings in two cases were indicative of epithelial differentiation. The tumors behaved aggressively; all five patients for whom there was clinical follow-up died of metastases within 40 months. The six anaplastic and sarcomatoid carcinomas were compared with 29 typical adenocarcinomas arising in the jejunum or ileum. Only two of the latter group had symptoms referable to distant metastases at presentation. These tumors also tended to be smaller at presentation (11 tumors were less than 4 cm in greatest dimension). Of 25 patients with typical adenocarcinomas who had acceptable follow-up, 18 (72%) died of disease and five (20%) were alive with no evidence of disease after 5 years. We conclude that anaplastic and sarcomatoid carcinoma is a rare variant of small intestinal carcinoma with an aggressive clinical course.